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Genetic and Histopathologic Evaluation of BRCA1 and BRCA2 DNA Sequence Variants of Unknown Clinical Significance

Douglas Easton¹¹, Sean V. Tavtigian⁹, David Goldgar⁸ and Amanda B. Spurdle¹

¹ Queensland Institute of Medical Research; ² Department of Pathology and ³ School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia; ⁴ Peter MacCallum Cancer Centre; ⁵ Department of Pathology and ⁶ Centre for Genetic Epidemiology University of Melbourne, Melbourne, Australia; ⁷ Myriad Genetic Laboratories, Inc.; ⁸ Department of Medical Informatics, University of Utah, Salt Lake City, Utah; ⁹ IARC, Lyon, France; ¹⁰ Molecular Diagnostics Lab., National Center for Scientific Research Demokritos, Athens, Greece; and ¹¹ Strangeways Laboratory, University of Cambridge, Cambridge, England

Requests for reprints: Amanda B. Spurdle, Queensland Institute of Medical Research, 300 Herston Road, QLD 4029, Brisbane, Queensland 4006, Australia. Phone: 617-33-620-371; Fax: 617-33-620-105; E-mail: mandyS{at}qimr.edu.au.

Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants. (Cancer Res 2006; 66(4): 2019-27)

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